This present invention relates to the process for preparing sodium ferric gluconate complex in sucrose.
1. Background of the Invention
Sodium ferric gluconate complex in sucrose has been known for about 40 years. It has been utilized primarily as an injectable agent for treating iron deficiencies in animals and human patients, having several advantages over other iron preparations including low toxicity, low incidence of adverse reactions, and satisfactory rate of iron absorption.
The material has been studied, see xe2x80x9cStudies on Iron Complexes Ixe2x80x9d, Yakugaku Zasshi Vol. 78, pp. 951-957 (1958); Tanabe and Okada, xe2x80x9cStudies on Iron Complexes IIxe2x80x9d, Takeda Kenkyusho Nempo, Vol. 21, pp. 1-10 (1962); Tanabe and Okada, xe2x80x9cStudies on Iron Complexes IIIxe2x80x9d, Takeda Kenkyusho Nempo, Vol. 21, pp. 11-19 (1962); and Tanabe and Okada, xe2x80x9cStudies on Iron Complexes IVxe2x80x9d, Takeda Kenkyusho Nempo, Vol. 21, pp. 20-25 (1962). Generally, the published methodology utilizes the reaction of iron hydroxide as the starting material.
2. The Problem in the Art
Literature methods of preparing sodium ferric gluconate complex in sucrose are not satisfactory, due to low yields and high cost of preparation.
This invention provides a process for preparing sodium ferric gluconate complex in sucrose using the following steps:
a) combining a ferric salt solution with a weak alkali chosen from the group consisting of alkaline earth metal and ammonium salts, such as sodium carbonate, sodium bicarbonate, lithium carbonate, potassium carbonate, potassium bicarbonate, ammonium carbonate, ammonium bicarbonate and mixtures thereof, to form the ferric oxyhydroxide;
b) combining ferric oxyhydroxide and sodium gluconate in solution to yield the sodium ferric gluconate complex;
c) isolating the sodium ferric gluconate complex; and
d) combining the sodium ferric gluconate with sucrose in solution to yield the desired sodium ferric gluconate complex in sucrose.
One key step in the process of this invention is the preparation of the ferric oxyhydroxide.
The ferric oxyhydroxide is prepared by neutralization of an aqueous solution of an iron (III) chloride salt with weak alkali at room temperature. This is in the form of colloidal gel, as the solid settles down and clear liquid remains at the top.
Although we do not wish to be bound by theory, the following is proposed as the scheme of formation of ferric oxyhydroxide.
FeCl3 (solid)+H2Oxe2x86x92Fe3++3Clxe2x88x92(in solution)
Fe3++H2O⇄Fe(OH)2++H+(weak acidic solution)
Fe(OH)2++H2O⇄Fe(OH)2++H+
Fe3++CO3xe2x88x922 (from sodium carbonate)+H2Oxe2x86x92Fe(OH)+2+HCO3xe2x88x921 (in solution)
Clxe2x88x921 (from ferric chloride)+Na+1(from sodium carbonate or sodium bicarbonate)xe2x86x92NaCl (in solution)
Clxe2x88x921 (from ferric chloride)+Li+1(from lithium carbonate)xe2x86x92LiCl (in solution)
Clxe2x88x921 (from ferric chloride)+K+1(from potassium carbonate or potassium bicarbonate)xe2x86x92KCl (in solution)
Clxe2x88x921 (from ferric chloride)+NH4+1(from ammonium carbonate or ammonium bicarbonate)xe2x86x92NH4Cl (in solution)
Fe(OH)+2+HCO3xe2x88x921+H2Oxe2x86x92Fe(OH)2+1+CO2↑(in solution)
(poly)Fe(OH)2+1+CO3xe2x88x922+H2Oxe2x86x92(poly)FeOOH (colloidal gel)+CO2↑
The byproducts of this weak base neutralization of weak acidic solution of ferric chloride are chloride salt and carbon dioxide.
When attempts were made to use either ammonium hydroxide or sodium hydroxide to neutralize the ferric chloride solution, the reactions failed to form sodium ferric gluconate complex with sodium gluconate.
The present invention relates to a method of making sodium ferric gluconate complex in sucrose, comprising the steps of:
a) combining an aqueous solution of ferric chloride with solid or aqueous weak alkali to a neutral pH;
b) removing chloride salts from colloidal ferric oxyhydroxide in solution;
c) adding sodium gluconate (solid) to the aqueous colloidal solution of ferric oxyhydroxide and heating to about 70-80xc2x0 C. for about 2 to 3 hours or until all ferric oxyhydroxide dissolves, and produces a dark brown color;
d) drying the sodium ferric gluconate complex, e.g., using freeze-drying; and
e) adding sucrose solution (about 20%) into the sodium ferric gluconate complex.
The starting materials for the reaction of this invention are:
Sucrose (xcex1-D-glucopyranoside, xcex2-D-fructofuranosyl-) is a disaccharide of formula C12H22O11 (molecular weight=342.30). CAS=57-50-1. Sucrose is a sugar obtained from saccharum fininarum Linne (family gramineae), Beta vulgaris Linne (family Chenopodiaceae), and other sources.
Sodium gluconate (D-gluconic acid, monosodium salt) is of formula C6H11NaO7 (molecular weight=218.14).
The iron salt used as the starting material can be any which is available. We choose ferric salts to minimize expense. The ferric salt is preferably ferric chloride hexahydrate, although other ferric chloride forms or ferric salts can be used.
In the first step of the process of the invention, ferric chloride hexahydrate is dissolved in water and adding quantitatively the weak base such as carbonate salt solution to neutral pH to precipitate ferric oxyhydroxide. The colloidal ferric oxyhydroxide is formed along with chloride salts in solution.
The weak base can be chosen from the group consisting of alkaline earth metal and ammonium salts, such as sodium carbonate, sodium bicarbonate, lithium carbonate, potassium carbonate, potassium bicarbonate, ammonium carbonate, ammonium bicarbonate and mixtures thereof. It can be employed either as a solid added to the aqueous solution of the ferric chloride or in aqueous solution. It is used in quantitative amounts to the ferric chloride.
In the next step, chloride salt is removed by several times washing with deionized water, which is pipetted out or siphoned off.
The washed ferric oxyhydroxide is then suspended in water and solid sodium gluconate is added. The ratio of ferric salt to sodium gluconate is 2:1, although the ratio can be as low as 1.5 to 1, or as high as 4:1. The solution is then heated to about 70-80xc2x0 C. for about 2 to 3 hours or until all ferric oxyhydroxide dissolves. The product has a dark brown color. The critical end point of this step is the dark brown color and the complete solubility of the product. When the reaction is unsuccessful, the product is a reddish or light brown; the reaction mixture has visible solids.
Once the reaction is complete, the product is dried, e.g., by freeze-drying. The material is identified by infrared spectroscopic analysis. This material is then used in the next step.
In the next step, the sodium ferric gluconate complex is mixed with 20% of aqueous sucrose at a temperature of between 80xc2x0 C. and 100xc2x0 C., then cooled. This product in solution is useful as the injectable drug.
The above reactions are preferably performed in a dark place or in subdued light, although this is not critical to the success of the reactions.